# Cytosolic Delivery of a Bithiophene Derivative via Polymersomes Kills Trypanosoma cruzi Amastigotes and Modulates the Inflammatory Response

## TL;DR

A new nanocarrier system delivers a drug to kill the parasite causing Chagas disease and reduces inflammation, offering a potential treatment for chronic cases.

## Contribution

A polymersome-based delivery system for a bithiophene derivative that effectively targets T. cruzi amastigotes and modulates inflammation.

## Key findings

- BTAc-loaded polymersomes showed high efficacy against three T. cruzi strains with IC50 values of 6.17, 24.01, and 30.68 μg/mL.
- The formulation reduced proinflammatory cytokines to basal levels, indicating immunomodulatory potential.
- Förster Resonance Energy Transfer analysis confirmed cytosolic delivery of BTAc, bypassing endosomes.

## Abstract

Chagas disease, caused
by the protozoan Trypanosoma
cruzi, is an infectious illness that progresses through acute,
indeterminate,
and chronic phases. The acute phase often presents mild symptoms,
followed by an asymptomatic indeterminate phase. In some cases, the
disease advances to chronic Chagas cardiomyopathy, driven by sustained
inflammation. Current treatments, benznidazole and nifurtimox, have
limited efficacy in this stage and are associated with significant
toxicity, highlighting the need for better therapies. PEG-b-PPS loaded with BTAc, exhibited favorable
physicochemical properties, including high stability and an average
size of 120 nm, suitable for efficient uptake by phagocytic cells
such as macrophages. BTAc-loaded polymersomes showed
enhanced efficacy against intracellular amastigotes of three T. cruzi strains (CL Brener, Brazil and Y) with IC50 values of 6.17, 24.01, and 30.68 μg/mL, respectively. The
formulation simultaneously reduced proinflammatory cytokines to basal
levels, suggesting an immunomodulatory potential. Importantly, Förster
Resonance Energy Transfer analysis confirmed that BTAc-loaded polymersomes remain intact upon cellular uptake, escape the
endosomal compartment, and release their payload directly into the
cytosol, which is the intracellular niche where amastigotes persist
during chronic infection. These findings underscore the potential
of this nanocarrier system as an innovative approach that combines
targeted antitrypanosomal therapy with enhanced immunomodulation,
offering a promising strategy for the treatment of chronic Chagas
disease.